The leading cause of mortality among diabetic patients in the United States is heart disease. Despite the numerous effects diabetes exerts on the cardiovascular system, there is substantial evidence indicating that a diabetes-specific cardiomyopathy occurs in the absence of coronary artery disease or hypertension (see, e.g., Ahmed (1975) Am. Heart J. 89:153-158; Galderisi (1991) Am. J. Cardiol. 68:85-89). Diabetic cardiomyopathy is characterized by impaired cardiac contractility and poor myocardial performance without an attendant vascular or valvular disease and can lead to congestive heart failure. Studies in diabetic human patients and animal models have demonstrated the early development of diastolic dysfunction prior to the alteration of systolic function (see, e.g., Fein (1980) Cir. Res. 47:922-933, Zarich (1988) J. Am. Coll. Cardiol. 12:114-120). Eventually, however, nearly all aspects of cardiac contractility appear to become impaired (see, e.g., Trost (2002) Diabetes 51:1166-1171, Penpargkul (1981) J. Mol. Cell. Cardiol. 13:303-309). Abnormalities in cardiac Ca2+ handling may be an important contributor to decreased contractile function in the diabetic heart.
Diabetic hyperglycemia results in a number of pathophysiological changes in the vascular system, but investigations of its role in diabetic cardiomyopathy are limited, but investigations of its role in diabetic cardiomyopathy are limited. Studies exposing cardiac myocytes to elevated extracellular glucose resulted in impaired cardiomyocytes contractility and calcium flux (see, e.g., Ren (1997) Am. J. Physiol. 273, H2876-2883) and increased [Ca2+]I Gupta (1993) Biophys. J. 65:2547-2558). The observation that the diastolic dysfunction observed in myocytes exposed to elevated extracellular glucose could be duplicated by incubation of cardiomyocytes with glucosamine, a precursor to cellular N- and O-linked glycosylation, suggested that the mechanism may involve increased flux of glucose into the hexosamine pathway (Ren (1997) supra). Increased hexosamine flux is known to lead to insulin resistance in many tissues (see, e.g., Marshall (1991) J. Biol. Chem. 266:4706-4712), and recent studies indicate that dynamic O-GlcNAcylation (the dynamic addition and removal of a single O-linked N-acetylglucosamine residue) may prove to be an important player in diabetes (see, e.g., Vosseller (2002) Proc. Natl. Acad. Sci. USA 99:5313-5318; Parker (2003) J. Biol. Chem. 278:10022-10027.